This invention relates to a process for the preparation of .alpha.-L-aspartyl-L-phenylalanine methyl ester (.alpha.-APM). .alpha.-APM is well known for its usefulness as a sweetening agent.
Synthesis of .alpha.-APM, according to a previous invention of U.S. Pat. No. 4,173,562, proceeds by the reaction of an N-protected L-aspartic anhydride and L-phenylalanine to afford N-protected .alpha.-L-aspartyl-L-phenylalanine. The protecting group which is used to shield the nitrogen of the amino group of the aspartic acid may be any of those known to persons skilled in the art, as exemplified by formyl, acetyl, benzoyl, substituted and unsubstituted carbobenzoxy, t-butoxycarbonyl, hydrohalide salt and the like. Particularly preferred is the formyl group. Thus, N-formyl-L-aspartic anhydride (FAA) is the preferred material which is coupled with L-phenylalanine to afford N-formyl-.alpha.-L-aspartyl-L-phenylalanine (FAP). In the reaction of FAA and phenylalanine to afford FAP, both the .alpha.- and .beta.-isomers of FAP are obtained. The .alpha.-isomer is then separated from the mixture of isomers and the .alpha.-FAP thus-obtained is treated to remove the protecting group. As set forth in our U.S. patent described above, any method suitable for removing the protecting groups from amines is appropriate.
After removal of the protecting group, the .alpha.-L-aspartyl-L-phenylalanine (.alpha.-AP) is esterified in methanolic hydrogen chloride to afford the hydrochloride salt of the methyl ester of .alpha.-L-aspartyl-L-phenylalanine (.alpha.-AMP.HCl). The .alpha.-APM.HCl is then neutralized with aqueous caustic to afford .alpha.-L-aspartyl-L-phenylalanine methyl ester (.alpha.-APM).
In Japanese patent publication 8097812, assigned to Teijin, Ltd., a two-step process for recovering amino acids is disclosed wherein the mother liquor from the coupling of a blocked aspartic anhydride and the methyl ester of L-phenylalanine was hydrolyzed with aqueous mineral acid and the pH of the solution was adjusted to pH 6 to precipitate L-phenylalanine and then to pH 2 to precipitate L-aspartic acid. In this publication, however, the recovery procedure is concerned with recovering amino acids from a completely different mother liquor than that which is utilized by the present invention.
In the publication described above, only the mother liquor from the initial coupling step is used as a source for recovery of L-phenylalanine and L-aspartic acid. Further, the procedure involves only the two-step precipitation of amino acids from the hydrolysis solution. It has been discovered that direct application of the two-step separation process of the Japanese publication to the reaction mixtures of the present invention does not afford amino acids of as high purity as the process of the present invention.